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DOI	10.1073/pnas.2108359118
	High-risk human papillomavirus-18 uses an mRNA sequence to synthesize oncoprotein E6 in tumors
	García A.; Maldonado G.; González J.L.; Svitkin Y.; Cantú D.; García-Carrancá A.; Sonenberg N.; Hernández G.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:41
英文摘要	Cervical cancer is the fourth most common cause of cancer in women worldwide in terms of both incidence and mortality. Persistent infection with high-risk types of human papillomavirus (HPV), namely 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68, constitute a necessary cause for the development of cervical cancer. Viral oncoproteins E6 and E7 play central roles in the carcinogenic process by virtue of their interactions with cell master proteins such as p53, retinoblastoma (Rb), mammalian target of rapamycin (mTOR), and c-MYC. For the synthesis of E6 and E7, HPVs use a bicistronic messenger RNA (mRNA) that has been studied in cultured cells. Here, we report that in cervical tumors, HPV-18, -39, and -45 transcribe E6/E7 mRNAs with extremely short 5′ untranslated regions (UTRs) or even lacking a 5′ UTR (i.e., zero to three nucleotides long) to express E6. We show that the translation of HPV-18 E6 cistron is regulated by the motif ACCaugGCGCG(C/A)UUU surrounding the AUG start codon, which we term Translation Initiation of Leaderless mRNAs (TILM). This motif is conserved in all HPV types of the phylogenetically coherent group forming genus alpha, species 7, which infect mucosal epithelia. We further show that the translation of HPV-18 E6 largely relies on the cap structure and eIF4E and eIF4AI, two key translation initiation factors linking translation and cancer but does not involve scanning. Our results support the notion that E6 forms the center of the positive oncogenic feedback loop node involving eIF4E, the mTOR cascade, and p53. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Cancer; E6; HPV; TILM; Translation
语种	英语
scopus关键词	initiation factor 4A; initiation factor 4E; mammalian target of rapamycin; messenger RNA; Myc protein; protein E6; protein E7; protein p53; DNA binding protein; E6 protein, Human papillomavirus type 18; E7 protein, Human papillomavirus type 18; EIF4A1 protein, human; EIF4E protein, human; initiation factor 4A; initiation factor 4E; messenger RNA; MTOR protein, human; oncoprotein; protein p53; target of rapamycin kinase; TP53 protein, human; virus RNA; 5' untranslated region; Article; carcinogenicity; cistron; controlled study; disease course; epithelium; feedback system; female; genetic conservation; genus; human; human cell; Human papillomavirus type 18; Human papillomavirus type 39; Human papillomavirus type 45; human tissue; nonhuman; nucleotide motif; phylogeny; protein expression; protein synthesis; regulatory sequence; RNA sequence; start codon; translation initiation; uterine cervix cancer; virus transcription; Wart virus; biosynthesis; gene expression regulation; genetics; HaCat cell line; HEK293 cell line; HeLa cell line; Human papillomavirus type 18; metabolism; pathology; tumor cell line; uterine cervix tumor; virology; 5' Untranslated Regions; Cell Line, Tumor; Codon, Initiator; DNA-Binding Proteins; Eukaryotic Initiation Factor-4A; Eukaryotic Initiation Factor-4E; Female; Gene Expression Regulation, Viral; HaCaT Cells; HEK293 Cells; HeLa Cells; Human papillomavirus 18; Humans; Oncogene Proteins, Viral; Peptide Chain Initiation, Translational; RNA, Messenger; RNA, Viral; TOR Serine-Threonine Kinases; Tumor Suppressor Protein p53; Uterine Cervical Neoplasms
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/251004
作者单位	Unit of Biomedical Research on Cancer, Laboratory of Translation and Cancer, National Institute of Cancer (Instituto Nacional de Cancerología), Mexico City, 14080, Mexico; Unit of Biomedical Research on Cancer, Laboratory of Virus and Cancer, National Institute of Cancer (Instituto Nacional de Cancerología), Mexico City, 14080, Mexico; Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Unit of Biomedical Research on Cancer, Division of Basic Research, National Institute of Cancer, Mexico City, 14080, Mexico; Institute of Biomedical Research, Universidad Nacional Autónoma de México, Mexico City, 04510, Mexico
推荐引用方式 GB/T 7714	García A.,Maldonado G.,González J.L.,et al. High-risk human papillomavirus-18 uses an mRNA sequence to synthesize oncoprotein E6 in tumors[J],2021,118(41).
APA	García A..,Maldonado G..,González J.L..,Svitkin Y..,Cantú D..,...&Hernández G..(2021).High-risk human papillomavirus-18 uses an mRNA sequence to synthesize oncoprotein E6 in tumors.Proceedings of the National Academy of Sciences of the United States of America,118(41).
MLA	García A.,et al."High-risk human papillomavirus-18 uses an mRNA sequence to synthesize oncoprotein E6 in tumors".Proceedings of the National Academy of Sciences of the United States of America 118.41(2021).